Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 20
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Curr Drug Metab ; 20(9): 701-713, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31453781

RESUMO

BACKGROUND: Traditional Chinese medicine (TCM) has been used for medical purposes since the ancient time and has gradually gained recognition worldwide. Nowadays, patients with thrombus presiding to anticoagulant/ antiplatelet drugs prefer taking TCM. However, an increasing number of studies on herb-drug interactions have been shown. Nevertheless, findings are frequently conflicting and vague. In this review, we discuss the herb-drug interactions between TCM and anticoagulant/antiplatelet drugs to provide guidance on concomitant ingestion with anticoagulant/antiplatelet drugs. METHODS: We undertook a structured search of medicine and drug databases for peer-reviewed literature using focused review questions. RESULTS: Danshen, Ginkgo, Ginger, H. Perforatum, SMY and Puerarin injection had directional regulation effects on the efficacy of anticoagulant drugs by altering the CYPs, pharmacokinetic indexs and hemorheological parameters. H. Perforatum inhibited the efficacy of Clopidogrel by enhancing the CYP3A4 activity and Ginkgo increased the efficacy of Ticlopidine. Additionally, Renshen, the formulae except SMY and injections except Puerarin injection could increase or decrease the efficacy of anticoagulant/antiplatelet drugs via regulating the CYPs, platelet aggregation, hemorheological parameters and others. CONCLUSION: Some cases have reported that TCMs may increase the bleeding risk or has no effect on coagulation when anticoagulant/antiplatelet drugs are concurrently used. However, pharmacokinetic studies have presented either consistent or slightly varying results. So it is difficult to ascertain whether the concurrent use of TCM may increase or reduce the pharmacologic effects of anticoagulant/antiplatelet drugs with adverse reactions. Therefore, herb-drug interactions of TCM and anticoagulant/antiplatelet drugs should be further explored and defined.

2.
J Neuroimmunol ; 320: 80-86, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29759144

RESUMO

Tropisetron, an antagonist of serotonin type 3 receptors (5-HT3Rs), has been investigated in colonic inflammatory process. Since substance P/neurokinin 1 receptor (SP/NK1R) signaling pathway plays a key role in several sensory neuronal inflammatory. We evaluated the anti-inflammatory activity of tropisetron in mice cerebral cortex, and discovered that it was a potential inhibitor in LPS-mediated neuron inflammation through SP/NK1R signaling pathway. We found that tropisetron significantly reduced the increased number of iba-1 positive microglia, down-regulated the gene transcription and protein expression of IL-1ß,IL-6 and TNF-α in LPS stimulated cerebral cortex. To characterize the inhibitory mechanism of tropisetron at the SP response in inflammation, we further examined the effect of tropisetron on NF-κB and SP/NK1R signaling pathway in the process of mice cerebral cortex inflammation. We found that tropisetron inhibited the gene transcription and protein expression of NF-κB, SP, NK1R via inhibiting 5-HT3R activity. These findings might provide new insights into the anti-inflammatory activities of 5-HT3R inhibitor tropisetron, which would be the interaction of serotonin receptor signaling and SP/NK1R pathway. These might highlight their potential to design novel therapeutic strategies to manage inflammatory diseases.


Assuntos
Expressão Gênica/efeitos dos fármacos , Inflamação/fisiopatologia , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tropizetrona/farmacologia , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Lipopolissacarídeos/toxicidade , Camundongos , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Receptores da Neurocinina-1/efeitos dos fármacos , Receptores da Neurocinina-1/metabolismo , Substância P/efeitos dos fármacos , Substância P/metabolismo
3.
Curr Med Chem ; 25(17): 1999-2008, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29345573

RESUMO

Recent advances in multiple omics technologies and the advent of massively parallel sequencing provide technical supports for the implementation of precision medicine. The precision medicine emphasizes that heterogeneous diseases can be well classified into more precise subtypes by the powerful detection methods and integration of clinical features, so that the clinicians should develop more accurate diagnosis and therapeutic strategies for the disease subtype population in an effort to maximize the efficacy and minimize the unnecessary side effects. Oncology is at the forefront of precision medicine, as malignant tumors have significant heterogeneity and are among the leading causes of death nationally and worldwide. The incidence and mortality of Hepatocellular Carcinoma (HCC), a kind of extraordinarily heterogeneous malignancy, have been increasing worldwide, making it a major public health concern. Such heterogeneity affects key signaling pathways, driving phenotypic variation, influences tumor evolution, and poses severe challenges to HCC treatment. The application of precision medicine will have certain impact on HCC diagnosis and treatment strategies. Herein, we summarize the updates and challenges in high-risk population screening, prevention, diagnosis, staging and therapy of HCC under the concept of precision medicine.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Imunoterapia , Neoplasias Hepáticas/tratamento farmacológico
4.
Toxicol Mech Methods ; 27(9): 687-696, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28701067

RESUMO

Veratrum nigrum L. (VN) is a poisonous traditional Chinese medicine herb present since thousands of years in China. Clinical studies have shown that VN has the ability to cause hepatotoxicity, which severely limits its clinical use. The mechanism of its hepatotoxicity has not been fully elucidated. The purpose of this study was to develop and characterize a model of acute and chronic hepatotoxicity induced by Veratrum nigrum L. extract (VNE) to understand the mechanism of liver tissue metabolomics approach using on ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOFMS). Mice were administered with VNE in the acute and chronic phases. Histopathologic inspections and biochemistry analysis disclosed severe liver damage after exposure to VNE. A partial least-squares discriminant analysis (PLS-DA) of the metabolomic profiles of rat liver tissues highlighted a number of metabolic disturbances induced by VNE, focusing on purine and pyrimidine metabolism, tryptophan metabolism, phospholipid metabolism, sphingolipid metabolism and fatty acid metabolism. These findings could well explain VNE-induced acute and chronic hepatotoxicity and reveal several potential biomarkers associated with this toxicity. This indicates that UHPLC-Q-TOFMS-based metabolomics approach demonstrated its feasibility and allowed a better understanding of VNE-induced liver toxicity dynamically.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Fígado/efeitos dos fármacos , Espectrometria de Massas/métodos , Metabolômica , Extratos Vegetais/toxicidade , Veratrum/química , Animais , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
5.
Am J Cancer Res ; 7(12): 2503-2514, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29312803

RESUMO

Sorafenib is currently the only approved first-line targeted drug against advanced hepatocellular carcinoma (HCC). However, unsatisfactory efficacy and resistance of sorafenib raises the urgent need to develop more effective therapeutic strategies for HCC. Here, we evaluated the effects of combination of histone deacetylase inhibitor Valproic acid (VPA) and sorafenib in HCC both in vitro and in vivo. Co-treatment of sorafenib and VPA synergistically inhibited HCC cell viability, induced cell apoptosis, along with the up-regulation of p21, Bax, cleaved caspase9, cleaved caspase3, cleaved PARP and down-regulation of Bcl-xL, suggesting this combination activated intrinsic apoptotic pathway. Our further experiment results showed that sorafenib plus VPA decreased tumor burden more effectively than sorafenib or VPA mono-therapy in nude mice subcutaneous xenograft model. Histological and serological analysis demonstrated well tolerance of this combination in vivo. On a molecular level, our results presented a possible crosstalk between Notch3 and Akt signaling. Sorafenib increased the expression of Notch3 in a dosage dependent manner, along with the phosphorylation of Akt in HCC cells. In comparison, this induction of Notch3 and pAkt could be decreased by VPA, implying that Notch3 and pAkt are of significance in the treatment of HCC, which may account for the synergism of sorafenib and VPA. In conclusion, the combination of sorafenib and VPA offers a potential targeting therapeutic regimen for HCC in the future.

6.
J Cancer ; 7(11): 1388-95, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27471554

RESUMO

Cervical cancer is a second leading cancer death in women world-wide, with most cases in less developed countries. Notch signaling is highly conserved with its involvement in many cancers. In the present study, we established stable cervical cell lines with Notch activation and inactivation and found that Notch activation played a suppressive role in cervical cancer cells. Meanwhile, the transient overexpression of the active intracellular domain of all four Notch receptors (ICN1, 2, 3, and 4) also induced the suppression of cervical cancer Hela cell growth. ICN1 also induced cell cycle arrest at phase G1. Notch1 signaling activation affected the expression of serial genes, especially the genes associated with cAMP signaling, with an increase of genes like THBS1, VCL, p63, c-Myc and SCG2, a decrease of genes like NR4A2, PCK2 and BCL-2. Particularly, The nuclear receptor NR4A2 was observed to induce cell proliferation via MTT assay and reduce cell apoptosis via FACS assay. Furthermore, NR4A2's activation could reverse ICN1-induced suppression of cell growth while erasing ICN1-induced increase of tumor suppressor p63. These findings support that Notch signaling mediates cervical cancer cell growth suppression with the involvement of nuclear receptor NR4A2. Notably, Notch/NR4A2/p63 signaling cascade possibly is a new signling pathway undisclosed.

7.
Br J Biomed Sci ; 73(3): 134-139, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27400196

RESUMO

BACKGROUND: The aims of this study were to investigate the effects of rivaroxaban on routine coagulation assays using our local, widely available, reagents and to study the relationship between sensitive coagulation assays and bleeding risk caused by rivaroxaban. METHODS: Prothrombin time (PT), activated partial thromboplastin time (APTT) and anti-factor Xa (FXa) chromogenic assays (Biophen DiXaI) and inhibition of FXa activity were performed in normal pooled plasma (NPP) spiked with rivaroxaban and plasma samples from patients treated with rivaroxaban. RESULTS: In vitro, the linear correlation coefficient of measured concentrations of rivaroxaban, by Biophen DiXaI, and spiked concentrations of rivaroxaban was 0.99. PT and APTT showed good linear correlation with rivaroxaban concentrations, while other assays showed poor correlation. In vivo, PT showed a moderate linear correlation with rivaroxaban concentrations while APTT had a weak correlation with rivaroxaban concentrations. In vitro and in vivo, the rivaroxaban concentrations, measured by Biophen DiXaI, always showed good correlation with the inhibition of FXa activity, and PT values showed moderate correlation with the inhibition of FXa activity. CONCLUSIONS: Biophen DiXaI can be considered as a quantitative method to monitor the anticoagulation activity of rivaroxaban, and could be used to evaluate bleeding risk caused by rivaroxaban. The PT reagent (Thrombosis S) could be considered as a rough method to monitor the anticoagulation activity of rivaroxaban and evaluate bleeding risk caused by rivaroxaban.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa/uso terapêutico , Rivaroxabana/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Trombose Venosa/prevenção & controle , Adulto Jovem
8.
J Drug Target ; 24(2): 169-77, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26211366

RESUMO

BACKGROUND: Human pancreatic carcinoids, a type of neuroendocrine tumors, are asymptomatic and difficult to diagnose, with the effects of traditional anti-cancer therapies being limited. The histone deacetylase (HDAC) inhibitor valproic acid (VPA) was evaluated for its effects alone and in combination with receptor-targeting peptide-drug conjugate via increasing drug internalization. MATERIALS AND METHODS: The in vitro and in vivo assays were used to evaluate the effects of VPA and somatostatin receptor-targeting camptothecin-somatostatin conjugate (CPT-SST). RESULTS: VPA induced proliferation suppression, cell apoptosis and cell cycle arrest. VPA acts as a HDAC inhibitor to induce a decrease of HDAC4 and an increase of acetylated histone 4 (AcH4). Meanwhile, most importantly, besides activating Notch signaling, VPA was observed to stimulate the expression of somatostatin receptor type 2 (SSTR2) that has been applied for receptor-targeting therapies. This characteristic was used for a combination therapy of VPA and CPT-SST. The combination displayed much more potent anti-tumor effects on carcinoid tumor growth by increasing SSTR2 density and drug internalization in target tumor cells. CONCLUSION: The combination of VPA and a SSTR2-targeting agent provides us a promising approach in treatment of carcinoid tumors.


Assuntos
Proliferação de Células/efeitos dos fármacos , Peptídeos/metabolismo , Receptores de Peptídeos/metabolismo , Receptores de Somatostatina/metabolismo , Ácido Valproico/farmacologia , Animais , Apoptose/efeitos dos fármacos , Camptotecina/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Camundongos , Camundongos Nus , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Receptores Notch/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais/efeitos dos fármacos
9.
J Cancer ; 6(10): 996-1004, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26366213

RESUMO

Hepatocellular carcinoma (HCC) is a type of malignant cancer. Notch signaling is aberrantly expressed in HCC tissues with more evidence showing that this signaling plays a critical role in HCCs. In the present study, we investigate the effects of the anti-convulsant drug valproic acid (VPA) in HCC cells and its involvement in modulating Notch signaling. We found that VPA, acting as a histone deacetylase (HDAC) inhibitor, induced a decrease in HDAC4 and an increase in acetylated histone 4 (AcH4) and suppressed HCC cell growth. VPA also induced down-regulation of Notch signaling via suppressing the expression of Notch1 and its target gene HES1, with an increase of tumor suppressor p21 and p63. Furthermore, Notch1 activation via overexpressing Notch1 active form ICN1 induced HCC cell proliferation and anti-apoptosis, indicating Notch signaling played an oncogenic role in HCC cells. Meanwhile, VPA could reverse Notch1-induced increase of cell proliferation. Interestingly, VPA was also observed to stimulate the expression of G protein-coupled somatostatin receptor type 2 (SSTR2) that has been used in receptor-targeting therapies. This discovery supports a combination therapy of VPA with the SSTR2-targeting agents. Our in vitro assay did show that the combination of VPA and the peptide-drug conjugate camptothecin-somatostatin (CPT-SST) displayed more potent anti-proliferative effects on HCC cells than did each alone. VPA may be a potential drug candidate in the development of anti-HCC drugs via targeting Notch signaling, especially in combination with receptor-targeting cytotoxic agents.

10.
Neuroreport ; 26(12): 723-7, 2015 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-26164461

RESUMO

Lamotrigine (LTG) has shown benefits in animal models of cerebral ischemia, but the mechanism involved was not fully studied. This study was carried out to examine the effects of LTG on cognitive dysfunction, ß-amyloid1-42 accumulation, and tau protein hyperphosphorylation in the hippocampus of ischemic rats. Transient ischemic stroke was induced by middle cerebral artery occlusion. The Morris water maze test was used to evaluate the cognitive function of rats. We found that LTG significantly attenuated ischemia-induced cognitive deficits and decreased neuronal injury in the hippocampal CA1 zone. Moreover, LTG reduced ß-amyloid1-42 and phosphorylated tau (AT8) in the hippocampus after ischemia. These results suggested that the cognition-protective effects of LTG after cerebral ischemia might involve inhibition of toxic ß-amyloid accumulation and tau hyperphosphorylation in the hippocampus.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Isquemia Encefálica/metabolismo , Transtornos Cognitivos/metabolismo , Hipocampo/metabolismo , Triazinas/uso terapêutico , Proteínas tau/metabolismo , Animais , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/prevenção & controle , Hipocampo/efeitos dos fármacos , Lamotrigina , Masculino , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Ratos , Ratos Sprague-Dawley , Triazinas/farmacologia
11.
Anticancer Agents Med Chem ; 15(7): 869-80, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25783965

RESUMO

Anti-cancer targeting drugs appear to be a new and powerful "weapon" for cancer therapies. These targeting drugs are directed against specific molecules that are over-expressed or where certain unique factors are aberrantly expressed either in cancer cells or in diseased cell sites. Compared with traditional chemotherapeutic drugs, these targeting drugs have the advantages of high specificity, efficacy and less side effects. Target therapy is a breakthrough and revolutionary advance in the field of cancer therapy. Tumor angiogenesis plays a key role in tumor growth and metastasis and the mutation of tyrosine kinases is also strongly associated with cancer progression. Thus, in this review, we will discuss the advances in the development of targeting anti-cancer drugs by narrowing it down to small molecule tyrosine kinase inhibitors, monoclonal antibodies against epidermal growth factor receptors belonging to the ErbB family of receptor tyrosine kinases and angiogenic inhibitors. It will also address concerns for drug resistance and adverse events.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Humanos , Terapia de Alvo Molecular , Neoplasias/irrigação sanguínea , Neoplasias/metabolismo , Proteínas Tirosina Quinases/metabolismo
12.
Anticancer Agents Med Chem ; 15(7): 809-15, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25642981

RESUMO

Hepatocellular carcinoma (HCC) is one of the most malignant cancers, with the second highest cancer death rate world-wide, next to lung cancer. The signaling mechanisms in HCC are currently not clear. Notch signaling, which is highly conserved and plays a critical role in many cancers, was found to be aberrantly upregulated in HCC tissues compared to normal liver tissues. Accumulating evidence supports that Notch signaling plays a significantly important role in HCC carcinogenesis. This review discusses the functions of Notch signaling in HCC and its potential therapeutic applications against this cancer.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Receptores Notch/metabolismo , Animais , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/terapia , Terapia Combinada , Doxorrubicina/uso terapêutico , Técnicas de Silenciamento de Genes , Terapia Genética , Humanos , Neoplasias Hepáticas/terapia , Terapia de Alvo Molecular , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Receptores Notch/genética , Transdução de Sinais , Sorafenibe , Ácido Valproico/uso terapêutico
13.
Br J Pharmacol ; 171(4): 1054-67, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24283699

RESUMO

BACKGROUND AND PURPOSE: Voltage-activated Na(+) channels contain one distinct α-subunit. In the brain NaV 1.1, NaV 1.2, NaV 1.3 and NaV 1.6 are the four most abundantly expressed α-subunits. The antiepileptic drugs (AEDs) carbamazepine, phenytoin and lamotrigine have voltage-gated Na(+) channels as their primary therapeutic targets. This study provides a systematic comparison of the biophysical properties of these four α-subunits and characterizes their interaction with carbamazepine, phenytoin and lamotrigine. EXPERIMENTAL APPROACH: Na(+) currents were recorded in voltage-clamp mode in HEK293 cells stably expressing one of the four α-subunits. KEY RESULTS: NaV 1.2 and NaV 1.3 subunits have a relatively slow recovery from inactivation, compared with the other subunits and NaV 1.1 subunits generate the largest window current. Lamotrigine evokes a larger maximal shift of the steady-state inactivation relationship than carbamazepine or phenytoin. Carbamazepine shows the highest binding rate to the α-subunits. Lamotrigine binding to NaV 1.1 subunits is faster than to the other α-subunits. Lamotrigine unbinding from the α-subunits is slower than that of carbamazepine and phenytoin. CONCLUSIONS AND IMPLICATIONS: The four Na(+) channel α-subunits show subtle differences in their biophysical properties, which, in combination with their (sub)cellular expression patterns in the brain, could contribute to differences in neuronal excitability. We also observed differences in the parameters that characterize AED binding to the Na(+) channel subunits. Particularly, lamotrigine binding to the four α-subunits suggests a subunit-specific response. Such differences will have consequences for the clinical efficacy of AEDs. Knowledge of the biophysical and binding parameters could be employed to optimize therapeutic strategies and drug development.


Assuntos
Subunidades Proteicas/fisiologia , Canais de Sódio/fisiologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Anticonvulsivantes/farmacologia , Encéfalo/fisiologia , Carbamazepina/farmacologia , Células HEK293 , Humanos , Lamotrigina , Fenitoína/farmacologia , Triazinas/farmacologia
14.
Chem Biol Interact ; 206(1): 100-8, 2013 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-23994249

RESUMO

Nuclear factor-E2-related factor 2 (Nrf2) is an important cytoprotective transcription factor which plays a key role in antioxidant and detoxification processes. Recent studies have reported that development of chemoresistance is associated with the constitutive activation of the Nrf2-mediated signaling pathway in many types of cancer cells. Here, we investigated whether Nrf2 was associated with drug resistant in doxorubicin resistant BEL-7402 (BEL-7402/ADM) cells, and if chrysin could reverse drug resistance in BEL-7402/ADM cells. We found that remarkable higher level of Nrf2 and its target proteins in BEL-7402/ADM cells compared to BEL-7402 cells. Similarly, intracellular Nrf2 protein level was significantly decreased and ADM resistance was partially reversed by Nrf2 siRNA in BEL-7402/ADM cells. chrysin is a potent Nrf2 inhibitor which sensitizes BEL-7402/ADM cells to ADM and increases intracellular concentration of ADM. Mechanistically, chrysin significantly reduced Nrf2 expression at both the mRNA and protein levels through down-regulating PI3K-Akt and ERK pathway. Consequently, expression of Nrf2-downstream genes HO-1, AKR1B10, and MRP5 were reduced and the Nrf2-dependent chemoresistance was suppressed. In conclusion, these results clearly indicate that activation of Nrf2 is associated with drug resistance in BEL-7402/ADM cells and chrysin may be an effective adjuvant sensitizer to reduce anticancer drug resistance by down-regulating Nrf2 signaling pathway.


Assuntos
Doxorrubicina/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Flavonoides/farmacologia , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Relação Dose-Resposta a Droga , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
15.
Biol Pharm Bull ; 36(4): 548-55, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23337128

RESUMO

Vascular endothelial growth factor (VEGF), an angiogenic factor, was found to modulate synaptic plasticity by affecting K(+) and Ca(2+) channels and protect neuron from death by depressing glutamatergic transmission. However, whether VEGF also modulates neuronal activity through modulating voltage-gated Na(+) channels (VGSCs), a main determinant of neuronal excitability, we observed the effects of VEGF on Na(+) channel properties and function on cultured rat hippocampal neurons through whole-cell patch-clamp recording. We found that VEGF decreased the Na(+) channel excitability by shifting the voltage-dependence of steady-state inactivation to more hyperpolarized direction, and increasing the time constants of recovery from inactivation without significantly affecting the activation process. The effect of VEGF on Na(+) channel steady-state inactivation was inhibited by the specific VEGF Flk-1 receptor antagonist SU1498, but was not affected by protein kinase C (PKC)-activator 1-oleoyl-2-acetyl-sn-glycerol (OAG). Furthermore, the inhibition of Na(+) currents by VEGF was frequency-dependent. In addition, the frequency of neuron firing evoked by current injection was reversibly depressed by VEGF. Therefore, our results suggest a potential role of VGSCs in the modulation of VEGF on neuronal excitability.


Assuntos
Neurônios/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/farmacologia , Canais de Sódio Disparados por Voltagem/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Células Cultivadas , Hipocampo/citologia , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley
16.
Neurochem Int ; 56(8): 955-61, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20398714

RESUMO

This study investigated whether exacerbation of poststroke dementia by diabetes associated abnormal tau phosphorylation and its mechanism. Streptozotocin (STZ) injection and/or a high fat diet (HFD) were used to treat rats to induce type 1 and 2 diabetes. Animals were randomly divided into STZ, HFD, STZ-HFD, and normal diet (NPD) groups. Focal ischemic stroke was induced by middle cerebral artery occlusion (MCAO). Cognitive function was tested by the Morris water maze. STZ or STZ-HFD treatment exacerbated ischemia-induced cognitive deficits, brain infarction and reduction of synaptophysin expression. Moreover, we found that diabetes further increased AT8, a marker of hyperphosphorylated tau, protein and immunopositive stained cells in the hippocampus of rats following MCAO while reduced the level of phosphorylated glycogen synthase kinase 3-beta at serine-9 residues (p-ser9-GSK-3beta), indicating activation of GSK-3beta. We conclude that diabetes further deteriorates ischemia-induced brain damage and cognitive deficits which may be associated with abnormal phosphorylation of tau as well as activation of GSK-3beta. These findings may be helpful for developing new strategies to prevent/delay formation of poststroke dementia in patients with diabetes.


Assuntos
Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Demência/metabolismo , Demência/patologia , Acidente Vascular Cerebral/metabolismo , Proteínas tau/metabolismo , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Infarto Cerebral/enzimologia , Infarto Cerebral/metabolismo , Infarto Cerebral/patologia , Cognição/fisiologia , Demência/etiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Masculino , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/patologia , Vesículas Sinápticas/metabolismo , Vesículas Sinápticas/patologia
17.
Neuropharmacology ; 54(2): 454-63, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18078964

RESUMO

Salicylate is the major metabolite and active component of aspirin (acetylsalicylic acid), which is widely used in clinical medicine for treating inflammation, pain syndromes and cardiovascular disorders. The well-known mechanism underlying salicylate's action mainly involves the inhibition of cyclooxygenase and subsequent decrease in prostaglandin production. Recent evidence suggests that salicylate also affects neuronal function through interaction with specific membrane channels/receptors. However, the effect of salicylate on synaptic and neural network function remains largely unknown. In this study, we investigated the effect of sodium salicylate on the synaptic transmission and neuronal excitation in the hippocampal CA1 area of rats, a key structure for many complex brain functions. With electrophysiological recordings in hippocampal slices, we found that sodium salicylate significantly enhanced neuronal excitation through reducing inhibitory GABAergic transmission without affecting the basal excitatory synaptic transmission. Salicylate significantly inhibited the amplitudes of both evoked and miniature inhibitory postsynaptic currents, and directly reduced gamma-aminobutyric acid type A (GABA(A)) receptor-mediated responses in cultured rat hippocampal neurons. Together, our results suggest that the widely used aspirin might impair hippocampal synaptic and neural network functions through its actions on GABAergic neurotransmission. Given the capability of aspirin to penetrate the blood-brain barrier, the present data imply that aspirin intake may cause network hyperactivity and be potentially harmful in susceptible subpopulations.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Salicilatos/farmacologia , Ácido gama-Aminobutírico/fisiologia , Animais , Células Cultivadas , Eletrofisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Hipocampo/citologia , Masculino , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos
18.
Mol Pharmacol ; 73(4): 1195-202, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18162605

RESUMO

In the mammalian cortex, alpha2 subunit-containing glycine receptors (GlyRs) mediate tonic inhibition, but the precise functional role of this type of GlyRs is difficult to establish because of the lack of subtype-selective antagonist. In this study, we found that cyclothiazide (CTZ), an epileptogenic agent, potently inhibited GlyR-mediated current (I(Gly)) in cultured rat hippocampal neurons. The inhibition was glycine concentration-dependent, suggesting a competitive mechanism. Note that GlyRs containing the alpha2 but not alpha1 or alpha3 subunits, when being heterologously expressed in human embryonic kidney 293T cells, were inhibited by CTZ, indicating subunit specificity of CTZ action. In addition, the degree of CTZ inhibition on I(Gly) in rat spinal neurons declined with time in culture, in parallel with a decline of alpha2 subunit expression, which is known to occur during spinal cord development. Furthermore, site-directed mutagenesis indicates that a single-amino acid threonine at position 59 near the N terminus of the alpha2 subunit confers the specificity of CTZ action. Thus, CTZ is a potent and selective inhibitor of alpha2-GlyRs, and threonine at position 59 plays a critical role in the susceptibility of GlyR to CTZ inhibition.


Assuntos
Anti-Hipertensivos/farmacologia , Benzotiadiazinas/farmacologia , Receptores da Glicina/antagonistas & inibidores , Animais , Linhagem Celular , Células Cultivadas , Hipocampo/efeitos dos fármacos , Hipocampo/embriologia , Hipocampo/metabolismo , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Proteínas Mutantes/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Picrotoxina/farmacologia , Células do Corno Posterior/efeitos dos fármacos , Células do Corno Posterior/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores da Glicina/metabolismo , Especificidade por Substrato/efeitos dos fármacos , Taurina/farmacologia , Treonina
19.
Epilepsia ; 48(4): 774-82, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17381447

RESUMO

PURPOSE: The transient and the persistent Na(+) current play a distinct role in neuronal excitability. Several antiepileptic drugs (AEDs) modulate the transient Na(+) current and block the persistent Na(+) current; both effects contribute to their antiepileptic properties. The interactions of the AEDs carbamazepine (CBZ) and topiramate (TPM) with the persistent and transient Na(+) current were investigated. METHODS: HEK293 cells stably expressing the alpha-subunit of the Na(+) channel Na(V)1.3 were used to record Na(+) currents under voltage-clamp by using the patch-clamp technique in whole-cell configuration and to investigate the effects of CBZ and TPM. RESULTS: The persistent Na(+) current was present in all cells and constituted 10.3 +/- 3.8% of the total current. CBZ partially blocked the persistent Na(+) current in a concentration-dependent manner [median effective concentration (EC(50)), 16 +/- 4 microM]. CBZ also shifted the steady-state inactivation of the transient Na(+) current to negative potentials (EC(50), 14 +/- 11 microM). TPM partially blocked the persistent Na(+) current with a much higher affinity (EC(50), 61 +/- 37 nM) than it affected the steady-state inactivation of the transient Na(+) current (EC(50), 3.2 +/- 1.8 microM). For the latter effect, TPM was at most half as effective as CBZ. CONCLUSIONS: The persistent Na(+) current flowing through the alpha-subunit of the Na(V)1.3 channel is partially blocked by CBZ at about the same therapeutic concentrations at which it modulates the transient Na(+) current, adding a distinct aspect to its anticonvulsant profile. The TPM-induced partial block of the persistent Na(+) current, already effective at low concentrations, could be the dominant action of this drug on the Na(+) current.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Anticonvulsivantes/farmacologia , Carbamazepina/farmacologia , Frutose/análogos & derivados , Canais de Sódio/efeitos dos fármacos , Potenciais de Ação/fisiologia , Encéfalo , Linhagem Celular , Células Cultivadas , Frutose/farmacologia , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Humanos , Canal de Sódio Disparado por Voltagem NAV1.5 , Condução Nervosa/efeitos dos fármacos , Condução Nervosa/fisiologia , Técnicas de Patch-Clamp , Canais de Sódio/fisiologia , Topiramato
20.
Acta Pharmacol Sin ; 27(12): 1537-46, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17112406

RESUMO

AIM: To study whether the functional properties of sodium channels, and subsequently the channel modulation by carbamazepine (CBZ) in hippocampal CA1 neurons can be changed after epileptic seizures. METHODS: We used the acutely dissociated hippocampal CA1 pyramidal cells from epilepsy model rats 3 weeks and 3 months respectively after kainate injection, and whole-cell voltage-clamp techniques. RESULTS: After long-term epileptic seizures, both sodium channel voltage-dependence of activation and steady-state inactivation shifted to more hyperpolarizing potentials, which resulted in the enlarged window current; the membrane density of sodium current decreased and the time constant of recovery from inactivation increased. CBZ displayed unchanged efficacy on sodium channels, with a similar binding rate to them, except that at higher concentrations, the voltage shift of inactivation was reduced. For the short-term kainate model rats, no differences were detected between the control and epilepsy groups. CONCLUSION: These results indicate that the properties of sodium channels in acutely dissociated hippocampal neurons could be changed following long-term epilepsy, but the alternation might not be enough to induce the channel resistance to CBZ.


Assuntos
Anticonvulsivantes/farmacologia , Carbamazepina/farmacologia , Epilepsia/metabolismo , Hipocampo/metabolismo , Canais de Sódio/metabolismo , Animais , Epilepsia/induzido quimicamente , Epilepsia/fisiopatologia , Hipocampo/patologia , Hipocampo/fisiologia , Ácido Caínico , Masculino , Potenciais da Membrana/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Canais de Sódio/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA